Biomedical subjects

J M Manson

Publications and source records attributed to J M Manson.

At least 37 records · Page 2Linked to original sources

PubMed1994

Embryotoxic effects of L-691,121, a class III antiarrhythmic agent, in rats.

L-691,121 is a class III antiarrhythmic agent which blocks potassium currents, leading to prolongation of cardiac potential and prevention of cardiac arrhythmia. In a developmental toxicity study in rats, there was a dose-dependent decrease in embryonic/fetal survival, and death of the entire litter was seen at an oral dose of 0.8 mg/kg per day. The critical period for embryolethality was determined as gestational days (GD) 10-13. In a study where females received 1 mg/kg on a critical day (GD 10 or 12) and were killed at 24-h intervals, a high embryonic mortality was seen at 72 h (GD 10 treatment) or 48 h (GD 12 treatment) after dosing. The surviving embryos had morphological abnormalities such as enlarged cardiac tube and pericardium, generalized edema, and hematoma. In order to investigate a possible mechanism for the embryolethality, GD 11 embryos were dissected from females at 4 h after dosing of 1 mg/kg and incubated for 5 h in vitro. The embryonic heart rates were decreased for the first 2 h after incubation but tended to recover to control levels thereafter. When GD 11 embryos were incubated for 4 h with the drug, there were decreases in the heart rates during the entire observation period. In a washout study where the embryos were transferred to drug-free medium after 1-h exposure, decreased heart rates recovered to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1993

Effects of the bisphosphonate, alendronate, on parturition in the rat.

Alendronate is a bisphosphonate which inhibits bone resorption. In female fertility studies in rats, dosages of 10 and 15 mg/kg/day produced physical signs of toxicity at parturition, including tremors, dystocia, and death in the dams and these were associated with neonatal deaths. These effects were associated with hypocalcemia in the dams but the fetuses were normocalcemic. There was no one critical period of treatment during gestation for these effects; they were instead proportional to length of treatment. Neonatal deaths were due to protracted deliveries rather than a direct effect of alendronate on the pups. Intravenous calcium supplementation (9.3 mg/dam) prevented the above-described adverse effects on dams and pups. In rats, fetal skeletal ossification is at its greatest rate in late gestation, and during this period free calcium is preferentially transported to the fetal compartment. The females meet this increased demand by calcium mobilization via increased bone resorption. We conclude that the maternotoxicity of alendronate in rats is due to the designed pharmacologic activity of this bisphosphonate; the drug prevents bone resorption and thereby denies the dam an important source of calcium at a time when fetal demand for this mineral is at its peak. The alendronate-induced hypocalcemia adversely affects parturition because uterine muscle contraction is a calcium-dependent process.

Alendronate↗

PubMed1993

Relief of metastatic biliary obstruction by stent placement: is it worthwhile?

Twenty-one patients undergoing stent placement for extra-hepatic biliary obstruction by metastatic disease were reviewed. Primary tumours (colorectal 8, stomach 4, breast 2, ovary 2, others 5) had been diagnosed 13 months (median) before presentation with bile duct obstruction, which was at the porta hepatis or common hepatic duct in 14 patients and in the common bile duct in seven. Endoscopic stent placement was achieved in 14 out of 20 patients in whom it was attempted. A percutaneous trans-hepatic procedure was necessary in five patients. Two patients could not be stented. Median survival was 5 months (range 1 month to 6 years) in patients stented successfully but only 1 month (2 weeks to 3 months) in unsuccessful cases (P < 0.01). Nine patients survived more than 4 months. Patients with proximal obstruction fared less well than those with distal obstruction; they required more procedures and survived for shorter periods (median 1 month versus 5 months, P < 0.05). Worthwhile palliation is afforded to almost half these patients by endoscopic stent placement and individual patients may achieve prolonged, symptom-free survival.

Adult↗

PubMed1993

Variation among individual White-Leghorn hens in the concentration of minerals in the albumen and yolk content of their eggs.

1. The mineral composition of the albumen and yolk was determined in several eggs from each of a number of individual hens from the same White-Leghorn strain. X-ray fluorescent spectrometry was used to undertake two independent series of analyses. A total of 8 minerals (calcium, chlorine, iron, magnesium, phosphorus, potassium, sodium, sulphur) were included in the analyses of the yolk and the same minerals, but excluding iron (which is present in only small amounts), in the albumen. 2. There was considerable variation between individuals in the mineral concentration in their eggs (coefficients of variation ranged between 3.8% for sodium to 19.9% for calcium in the albumen, and between 4.3% for phosphorus to 11.8% for iron in the yolk). 3. At the same time, the moderately high repeatability of mineral concentration (t = 0.4-0.6) in successive eggs from the same hen for several of the minerals analysed is indicative of some positive control by the hen of the mineral composition of her eggs. 4. There was a highly significant correlation (P < or = 0.001) between the mean concentration of potassium in the albumen and the hatchability of the eggs, supporting the claim that a deficiency of potassium in the egg could be the basis of some failures in hatchability. 5. The study also revealed variation among individual birds in the concentration of iron in the yolk which was negatively correlated (P < or = 0.01) with hatchability. No clear basis could be suggested for this variation among individual birds.

Animals↗

PubMed1992

Effects of in vivo endotoxin infusions on in vitro cellular immune responses in humans.

Studies of the immune response of patients following major injury have identified significant abnormalities, some of which may be due to the effects of endotoxin. To evaluate the effect of endotoxin on the immune system without conflicting variables, we studied 18 normal, healthy male volunteers each on two occasions. In one study, Escherichia coli endotoxin was administered intravenously at a dose of 4 ng/kg. In the other, saline was given. Blood for immune function studies was obtained at either 0, 4, or 24 hr (seven volunteers), 0, 1, and 4 hr (five volunteers), or 0, 4, and 6 hr (six volunteers) postinfusion. Peripheral blood mononuclear cells (PBMC) were isolated and adjusted to the same concentration. Measurements following endotoxin infusion were compared with those of the same volunteers following saline infusion and with those from normal ambulatory laboratory volunteers. Interleukin 1 (IL-1) production by adherent cells was significantly reduced at 1 hr post endotoxin infusion. Significant decreases in number of mononuclear cells, response to phytohemagglutinin (PHA), and production of IL-2 and IL-1 were observed by 4 hr after endotoxin infusion. No significant changes in percentages of monocytes, lymphocytes, or CD3, CD4, or CD8 lymphocytes were observed at any time. By 24 hr postinfusion all values had returned to normal or, in some cases, supranormal levels. Response to PHA by PBMC from volunteers 4 hr following endotoxin was completely restored by in vitro addition of recombinant human IL-2 but was only marginally improved by IL-1. In vitro addition of indomethacin to PBMC cultures responding to PHA reduced the suppression observed after in vivo endotoxin but also was not as effective as IL-2. In a fourth study, seven volunteers were treated as above either with two doses (800 mg each) of the cyclooxygenase inhibitor ibuprofen before endotoxin infusion or with ibuprofen alone. Ibuprofen pretreatment completely restored the PBMC response to PHA to normal and caused a significant decrease in the endotoxin-induced suppression of IL-2 production. However, the decrease in circulating PBMC number and adherent cell secretion of IL-1 was not affected by inhibition of the cyclooxygenase pathway. These results suggest that endotoxin has immunomodulatory effects on both adherent mononuclear-cell and T-lymphocyte function and that more than one mechanism is involved.

Adult↗

PubMed1989

The pharmacokinetics of the biliary excretion of ciprofloxacin.

The pharmacokinetics of ciprofloxacin excretion have been studied in 54 patients undergoing biliary and pancreatic operations with and without obstruction of the common bile duct. High concentrations were achieved in common duct bile within 20 minutes of intravenous injection and persisted for over 3 hours after 100 mg and for over 8 hours after 200 mg. The concentration of ciprofloxacin in the bile of functioning gall bladders was much greater than that in the common duct bile. Remarkably, it was identified in therapeutic concentrations in the bile of obstructed ducts. This and the rapid fall from initially high venous concentrations probably reflect diffusion from the circulation as a result of the exceptional tissue penetration. A unique feature of this study was the finding of clinically significant concentrations in the bile of obstructed ducts. Two patients developed wound infection and no side effects were observed. The broad spectrum antibiotic ciprofloxacin has potential as a useful agent for prophylaxis in biliary surgery maintaining biliary and venous concentrations in excess of the MIC90 for most biliary pathogens for more than 8 hours.

Adult↗

PubMed1989

Overview of a workshop on quantitative models for developmental toxicity risk assessment.

A workshop was held to discuss potential advancements to improve the precision of risk estimates for developmental toxicity. This paper presents an overview of the discussions at the workshop, focusing on the risk assessment process and science policy considerations important in the use of quantitative models. Some of the pertinent biological considerations are reviewed, particularly those related to the repair capacity of the developing organism and how this affects the concept of a threshold for developmental toxicity effects, as well as the maternal and litter influences on developmental toxicity outcomes. Finally, the current status of use of quantitative approaches is described, possible short-term approaches are discussed, and future research needs in this area are outlined.

Abnormalities, Drug-Induced↗

PubMed1988

Ovarian effects of an anti-inflammatory-immunomodulatory drug in the rat.

The purpose of this study was to determine whether a 30-day administration of SK&F 86002-A2, an inhibitor of cyclooxygenase and 5-lipoxygenase pathways of arachidonate metabolism, adversely affected reproductive cycles, ovarian structure, and/or pituitary/ovarian hormone secretion. Cyclooxygenase and 5-lipoxygenase enzymes catalyze the reactions leading to the synthesis of prostaglandins and leukotrienes, respectively, which are physiological regulators of ovarian function. Female rats were dosed once daily by gavage with 0, 1, 5, 10, 30, or 60 mg (base)/kg/day of SK&F 86002-A2 for 30 consecutive doses beginning on the day of vaginal proestrus. Vaginal smears were then examined daily until necropsy, when ovaries and uteri were collected for macroscopic and histological examination. In addition, serum concentrations of estradiol, progesterone, luteinizing hormone, follicle stimulating hormone, and prolactin were estimated by radioimmunoassay. Estrous cycle irregularity, resulting from a dose-related lengthening of the interestrous interval, significantly (p less than 0.05) reduced the number of cycles in rats receiving 60 mg/kg/day of SK&F 86002-A2 compared to controls. Furthermore, the ovaries from this group of rats weighed significantly more (p less than 0.05) than controls, apparently due to an increased occurrence of enlarged, cystic follicles that occasionally contained blood. Luteinized follicles with entrapped ova were also detected during histological examination. Dilatation of the uterine lumen was observed in some rats receiving doses of SK&F 86002-A2 greater than 1 mg/kg/day. Serum progesterone in rats receiving 60 mg/kg/day of SK&F 86002-A2 was significantly (p less than 0.05) lower than controls. In contrast, mean levels of serum estradiol were elevated in rats receiving 30 mg/kg/day of SK&F 86002-A2. Serum concentrations of FSH, LH, and prolactin were not significantly different in any group. The results of this study suggest that SK&F 86002-A2 disrupts cyclic ovarian function by a local, cumulative action that inhibits ovulation and alters steroid secretion.

Animals↗

PubMed1988

Ovarian effects of SK&F 86002-A2 in the rat: site of action.

In a preliminary 30-day study, oral administration of SK&F 86002-A2, an inhibitor of prostaglandin and leukotriene synthesis, blocked ovulation and altered ovarian structure and hormone production in rats. The purpose of the present study was to determine if the locus of action of SK&F 86002-A2 for these effects was the ovary or some other site in the female reproductive system, using a number of experimental approaches. A single sc or intraovarian injection of SK&F 86002-A2 did not block spontaneous or gonadotropin-induced ovulation in proestrous rats, whereas indomethacin, a positive control, acutely disrupted the ovulatory process. Since neither route of administration blocked ovulation, integrated pituitary and ovarian events were not negatively affected by a single injection of SK&F 86002-A2 at doses which caused ovarian dysfunction when administered repeatedly for 30 days. In contrast to a single dose, oral administration of SK&F 86002-A2 to hypophysectomized rats for 2 weeks suppressed follicular growth and estradiol production in response to sc administration of pregnant mare serum gonadotropin. Although ovarian function was suppressed in hypophysectomized rats, LH surges induced by estradiol in ovariectomized rats were not affected by administration of SK&F 86002-A2 for 2 weeks. Thus, hypothalamic/pituitary dysfunction did not contribute to the ovarian effects of SK&F 86002 that occurred after repeated dosing. In conclusion, these results indicate that disruption of ovarian cycles by SK&F 86002-A2 is related to a direct effect on the ovary, and not to altered hypothalamic/pituitary function and LH release. Specifically, SK&F 86002-A2 may suppress the ovarian response to gonadotrophin, retarding follicular growth and estrogen production. The ovarian effects are consistent with a pharmacological expression of the inhibitory action of SK&F 86002-A2 on prostaglandin and leukotriene synthesis.

Administration, Oral↗

PubMed1988

Inhibition of cyclo-oxygenase attenuates the metabolic response to endotoxin in humans.

Acute infection initiates fever, acute-phase changes, and catabolic responses in the host, resulting in weight loss, hypermetabolism, and accelerated proteolysis. To test the hypothesis that cyclo-oxygenase inhibition might attenuate these responses, we administered Escherichia coli endotoxin intravenously to seven normal volunteers and to seven additional subjects pretreated with a cyclo-oxygenase inhibitor (ibuprofen). Control studies were also performed following administration of saline and ibuprofen alone. Vital signs, metabolic rate, and concentrations of pituitary and stress hormones, as well as those of other substrates, were serially measured. Endotoxin administration produced a response similar to an acute illness, with flulike symptoms, fever, tachycardia, increased metabolic rate, and stimulation of stress hormone release. These changes were markedly attenuated by cyclo-oxygenase inhibition. The leukocytosis, hypoferremia, and elevation of the C-reactive protein level induced by endotoxin were unaffected by cyclo-oxygenase inhibition. These data indicate that activation of the cyclooxygenase pathway is necessary to produce many of the metabolic changes observed during critical illness.

Adult↗

PubMed1988

Metabolic effects of recombinant human growth hormone in patients receiving parenteral nutrition.

Recombinant human methionyl growth hormone (Protropin) (Genetech, Inc., San Francisco, CA) administered to normal volunteers receiving hypocaloric parenteral nutrition minimized weight loss and induced positive nitrogen balance. To evaluate whether growth hormone (GH) can promote anabolism in surgical patients, 11 stable malnourished individuals were studied. In the initial trial, subjects received a constant parenteral infusion of a hypocaloric diet that provided approximately 1100 kcal/24 hr and 1.3 g protein/kg/24 hr for at least 2 weeks. During 1 week, GH 10 mg was given subcutaneously daily, whereas the other week served as the control. Daily balance studies demonstrated that administration of GH resulted in significant retention of nitrogen (+3.4 g/24 h) and phosphorus (+218 mg/24 h), despite provision of only 60% of caloric requirements. With GH, serum blood urea nitrogen (BUN) and potassium fell, whereas glucose and insulin tended to rise, and levels of insulin-like growth factor 1 increased three to fourfold. Weight gain occurred with GH and was associated with positive mineral and water balance. Six patients received GH (10 mg subcutaneously daily) for 13-25 consecutive days after an initial control week. Significant nitrogen and phosphorus retention occurred over the entire period of GH administration, and no significant side effects were observed. In these depleted patients, GH caused significant and sustained nitrogen retention over a wide range of nutritional support. GH appears to enhance the efficacy of parenteral nutrition in stable individuals requiring repletion of body protein.

Adult↗

PubMed1988

Growth hormone stimulates protein synthesis during hypocaloric parenteral nutrition. Role of hormonal-substrate environment.

The influence of growth hormone (GH) on protein metabolism and fuel utilization was investigated in eight paired studies of normal volunteers. GH (10 mg) was given daily during one period, and saline was injected during control studies. For 6 days, subjects received parenteral nutrition that provided adequate dietary nitrogen, vitamin, and minerals, but energy intake varied to provide 30-100% of requirements. On Day 7, the feedings were discontinued and an oral glucose load (100 g) was administered. The level of energy intake did not markedly influence the actions of GH. During nutrient infusions, GH caused positive nitrogen balance (1.0 +/- 0.3 g/m2/day vs. -1.2 +/- 0.3 in controls, p less than 0.001) and increased protein synthesis (16.8 +/- 0.7 g N/m2/day vs. 13.9 +/- 0.8, p less than 0.01). No change in the rate of protein breakdown or excretion of 3-methylhistidine occurred. GH was associated with an increase in insulin and insulin-like growth factor-I concentrations (IGF-I, 9.1 +/- 0.6 IU/ml vs. 3.3 +/- 0.5, p less than 0.001). After discontinuation of the parenteral nutrition and administration of the oral glucose load, glucose concentrations tended to be higher after GH; however, despite a two- to threefold increase in insulin response, muscle glucose uptake was attenuated (1.10 +/- 0.19 g/kg forearm vs. 1.64 +/- 0.30 in controls, p less than 0.05). Compared with control conditions, GH appeared to attenuate the increase in amino acid nitrogen efflux from muscle after the administration of oral glucose. These data demonstrate that the protein anabolic effect of GH, which occurs even during hypocaloric feedings, is related to multiple mechanisms that favor protein synthesis. These include the increase in plasma concentrations of GH, insulin IGF-I and fat utilization. GH administration results in a hormonal-substrate environment that favors nitrogen retention and protein synthesis. GH may be beneficial in promoting protein synthesis in surgical patients, particularly in association with hypocaloric glucose infusions that allow utilization of body fat as an energy source.

Adult↗

PubMed1987

Developmental toxicity of halogenated acetonitriles: drinking water by-products of chlorine disinfection.

The developmental toxicity of acetonitrile and 5 halogenated derivatives was examined with an in vivo teratology screen adapted for use in the Long-Evans rat. The screen was extended to an evaluation of growth till postnatal Days 41-42, and weight of several organs at sacrifice. Acetonitrile was without developmental effects even at doses toxic to the dam. Of the halogenated compounds, treatment with trichloroacetonitrile (TCAN) and dichloroacetonitrile (DCAN) resulted in reduced fertility and increased early implantation failure. There was no effect on litter size in females bearing live litters, but pup birth weight was reduced in all litters exposed to halogenated compounds. Perinatal survival of the pups was adversely impacted by DCAN and TCAN. Postnatal growth till Day 4 was reduced by DCAN and bromochloroacetonitrile (BCAN) while growth till Day 42 was consistently affected only by TCAN. Some general observations were made on the usefulness of the criteria used in the screen, and TCAN, the most toxic of the halogenated compounds, was selected for further in-depth evaluation.

Abnormalities, Drug-Induced↗

PubMed1987

Effects of cefonicid and other cephalosporin antibiotics on male sexual development in rats.

The purpose of this study was to determine whether cefonicid, a cephalosporin antibiotic with a modified N-methylthiotetrazole (MTT) side chain, caused testicular toxicity when subcutaneously administered to Sprague-Dawley male rats from days 6 to 36 postpartum at doses of 50 to 1,000 mg/kg per day. Moxalactam (a cephamycin antibiotic which will be referred to as a cephalosporin for convenience throughout), which contains the MTT side chain, was used as a positive control and was administered at 100 to 1,000 mg/kg per day, and cephalothin, which lacks an MTT side chain, was used as the negative control at 1,000 mg/kg per day. Moxalactam caused a significant reduction in testicular and seminal vesicle weights in 37-day-old animals, and histological examination revealed bilateral multifocal atrophy of the seminiferous tubules at all dose levels. Animals reared to reproductive maturity had significant deficits in fertility, and histological examination revealed multifocal or diffuse atrophy of the seminiferous tubules at all doses with a severity greater than that observed in the 37-day-old animals. The histological findings were confirmed by marked reductions in testicular sperm production rates and cauda epididymal sperm numbers. Cephalothin and cefonicid had no treatment-related adverse effects on the sexual maturation of prepubertal, juvenile, or adult males. The absence (in cephalothin) or modification (in cefonicid) of the MTT side chain was not associated with adverse reproductive effects. The relevance of these findings to humans in prenatal and prepubertal stages of life cannot be determined at this time.

Age Factors↗

PubMed1986

Further characterization of the distribution and metabolism of nitrofen in the pregnant rat.

Nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) is an herbicide with potent teratogenic activity in rodent species. The present study was an extension of previous efforts to characterize the distribution and metabolism of nitrofen in pregnant rats. Following a single p.o. exposure to radiolabeled compound on day 10 of pregnancy, maternal and embryonic tissues were collected at intervals from 1.5 to 72 hours. Radioactivity was accumulated and retained in maternal fat for over 72 hours. Peak levels were reached in other maternal organs at 3-12 hours. The half-life in maternal plasma was estimated to be 42 hours. Radioactivity was first detected in the embryonic compartment at 3 hours and continued to increase through the 72-hour time point. HPLC analysis indicated that the parent compound is initially deposited in maternal fat and after 48 hours redistributes to other maternal organs and to the embryo. The 5-hydroxy derivative was the major nitrofen metabolite found in maternal tissues, while the 4'-amino and 4'-acetylamine derivatives were found at lower levels and all exhibited single-phase kinetics. The parent compound alone was found in the embryo, and levels increased gradually as nitrofen redistributed from the fat at 48 hours after exposure. The results of this and other studies of nitrofen metabolism in pregnant rats suggest that its teratogenicity is not mediated via generation of mutagenic intermediates through nitroreduction of the parent compound. Rather, the embryo is exposed to the parent compound alone and appears to be a deep compartment for accumulation of nitrofen.

Adipose Tissue↗

PubMed1986

Strain differences in response of Sprague-Dawley and Long Evans Hooded rats to the teratogen nitrofen.

Administration of nitrofen (2,4-dichloro-4'-nitrodiphenyl ether) during organogenesis in rodents produces neonatal lethality accompanied by lung hypoplasia, diaphragmatic hernias, heart anomalies, and hydronephrosis. Different strains of rats, Long Evans Hooded (LEH) and Sprague-Dawley (SD), are reported to have different malformation responses to prenatal exposure, which could be due to true strain differences, to different levels and times of exposure, or to the use of different methods for detecting visceral malformations. In the present study, LEH, SD, and "virus-antibody-negative" SD (VAN-SD) rats were identically exposed to 0, 6.25, 12.5, or 25 mg/kg/day of nitrofen by gavage in corn oil on days 6 15 of gestation. At term, half of the litter was examined by the Wilson method of razorblade sectioning and the remainder by a modified Staples method of fresh visceral examination. The two methods were equally sensitive for detecting diaphragm, kidney, and lung anomalies, whereas heart malformations were more frequently identified with fresh visceral examination. The frequency of total malformations did not vary across strains at any dose, but there were substantial differences in the pattern of malformations in each strain. SD and VAN-SD rats responded similarly for all malformations, but had significantly higher incidences of diaphragm and lung anomalies than LEH rats. Conversely, LEH rats had significantly elevated levels of kidney anomalies compared to SD and VAN-SD rats, whereas frequency of heart malformations was low and comparable across strains. These results suggest that true strain differences exist in the pattern of malformation produced by prenatal exposure to nitrofen that may be based on genetic differences in embryonic susceptibility.

Abnormalities, Drug-Induced↗

PubMed1986

Lack of in vivo mutagenicity and testicular toxicity of triamterene in mice.

Triamterene (2,4,7-triamino-6-phenylpteridine), a widely used diuretic/antihypertensive agent with weak antifolate activity, has been found to be positive in several in vitro assays for mutagenicity. The present studies were undertaken to characterize the potential mutagenic and antifolate activity of triamterene in the bone marrow and testes of mice with in vivo treatment. Triamterene had no clastogenic effects on the bone marrow at 6, 16, or 24 hr after a single oral dose of 25, 125, or 250 mg/kg. No alterations in hematopoietic cell maturation characteristic of antifolate action were observed in a dose-range study in which triamterene was orally administered to mice at 5-300 mg/kg/day for 5 days. Triamterene had no adverse effects on mating or fertility and did not induce dominant lethal mutations in the germ cells of male mice when given for 5 days at 5-100 mg/kg/day. Oral exposure to mice under identical conditions had no effect on testicular weight, DNA content, or activity of the de novo pathway for thymidine synthesis from deoxy [6-3H]uridine. The present findings are consistent with an absence of mutagenic effect and antifolate action on the bone marrow and testes with in vivo administration.

Animals↗

PubMed1986

Evaluation of the reproductive toxicology of 2,4,6-trichlorophenol in male and female rats.

The toxicity of chlorinated organic compounds which may be generated as a by-product of drinking water chlorination has been an issue of increasing concern. Relatively few data are available concerning their reproductive toxicity. The present study was designed to evaluate the reproductive effects of one of these compounds, 2,4,6-trichlorophenol (TCP), in male and female rats. Adult males were treated with either 0, 100, 500, or 1000 mg/kg of TCP (po) for 10 weeks, at which time semen evaluations were conducted on ejaculates recovered from the genital tract of receptive females. Fertility was assessed in the 0- and 1000-mg/kg groups. Females were treated with identical doses for 2 weeks prior to pregnancy then throughout gestation. Dams were allowed to litter and pup development was monitored until Day 42 postpartum. TCP had no effect on any sperm parameter or male fertility. Treatment of females with 1000 mg/kg of TCP produced gross maternal toxicity as reflected in increased lethality and decreased weight gains in the dams. However, no treatment-related differences were seen in litter sizes or pup survival. Male and female birth weights were significantly depressed in the 500- and 1000-mg/kg groups; these differences disappeared by Day 4 postpartum, suggesting that they were a reflection of maternal toxicity. To this extent, the reproductive processes of male and female rats do not appear to be a primary target for the effects of TCP.

Animals↗